Prostate cancer metastasizes from the prostate gland through lymphatic and hematogenous routes resulting in a high prevalence of metastases to regional nodes and bones. All metastatic cells must have an available supply of matrix proteases since proteolytic degradation is a vital process in metastasis. At least two central proteolytic systems are involved in prostate cancer metastasis---MMP-related and urokinase-related. This application addresses the role of the urokinase system, specifically the role of the urokinase receptor (uPAR) in prostate cancer progression. In collaboration with Dr. Jill Williams at the LSU-HSC in Shreveport, we have recently begun an analysis of uPAR in human prostate cancer specimens. Our initial results show an association between elevated uPAR expression and tumor grade in men undergoing prostatectomies. Additionally, we are finding a link between uPAR levels in the primary cancer and development of recurrent (metastatic) disease. Experimentally, the Principal Investigator has reported that PC-3-derived cell lines from mouse metastases show increased uPAR levels in vitro compared with parental PC-3s. In a tissue culture invasion assay, the Principal Investigator has shown that cells transiently transfected to express high levels of uPAR are more invasive than wild-type cells. Thus, human tissue data and in vitro experiments both suggest that prostate cancer cells which express high levels of uPAR possess an enhanced ability to metastasize. Since metastasis is a whole animal disease, the goals of this grant application are to investigate the role of elevated uPAR during prostate cancer progression in animals. Two specific aims are planned. In the first, the Principal Investigator will use intravenous and orthotopic injections to determine the effect of transient uPAR overexpression on primary tumor development, invasion and metastasis. In the second aim, the Principal Investigator will develop and employ an inducible system to up-regulate uPAR and use whole animal imaging to systematically determine the effects of uPAR levels and/or timing of uPAR induction on prostate cancer development and metastasis. These aims will allow us to understand how and when this key receptor promotes metastasis. Our long-term objective is to use this information to design more effective inhibitory strategies. This research is highly relevant to public health because prostate cancer is the most commonly diagnosed solid cancer in men and the metastatic disease can be managed only temporarily with patients generally succumbing within 3 years. [unreadable] [unreadable] [unreadable]